DESCRIPTION: (Applicant's Abstract) Nicotine addiction is a widespread disorder that contributes substantially to America's number one health problem: cigarette smoking. Nicotine addiction is a complex disorder with a genetic component, most likely polygenic in nature. Finding genes that contribute to the risk of nicotine addiction will require access to a very large population with the potential to enroll substantial numbers of affected subjects and make use of rapid and accurate phenotyping such as the Fagerstrom Test for Nicotine Dependence (FTND). In the proposed investigation, two separate samples will be drawn from an isolated population in Anqing, China: [1] 600 nicotine-addicted affected sib pairs (ASPs) and their parents, and [2] 500 unrelated cases (i.e., addicted smokers) and 500 unrelated controls (i.e., non-addicted smokers). The ASPs will be used for linkage studies using markers in a whole genome scan and for verifying the results of association studies; the cases and controls will be used for association studies with candidate genes, and with both genes and markers in areas identified by the linkage study. Specifically, with the ASPs, we will: [1] scan the genome with 10 cM resolution; [2] saturate promising regions with a dense set of markers; and [3] refine promising regions further through TDT analysis using customed-developed single nucleotide polymorphism (SNP) markers. With the 500 cases and 500 controls, we will perform SNP-based association studies for [1] previously reported nicotine addiction candidate genes, [2] genes involved in the biological pathways of nicotine metabolism, brain rewarding system, brain opioid system, and brain serotonergic system, and [3] positional candidate genes suggested by our linkage analysis. Once genetic variants involved in nicotine addiction have been defined, their predictive ability in a clinical setting can be tested in other populations. There are several unique advantages to carrying out this genetic study. [1] The population is quite isolated and homogeneous. [2] The study design is relatively comprehensive, including linkage and association analyses, state-of-the-art technologies, and powerful statistical methods. [3] The sample size is large, but all data will be rapidly and economically collected from a single geographic area. [4] The use of "super controls" (smokers with FTND-2) should add power to our case-control study. [5] Several large-scale genetic studies have already been successfully conducted in this region so the field team has been well trained and the necessary infrastructure has been established. [6] The local government and hospitals are highly enthusiastic and supportive of the proposed study.